Chair of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Berlin, 10623, Germany.
German Center for Infection Research (DZIF), Charitéplatz 1, 10117, Berlin, Germany; Institute of Virology, Charité-Universitätsmedizin Berlin, 10117, Germany.
Antiviral Res. 2024 Jun;226:105879. doi: 10.1016/j.antiviral.2024.105879. Epub 2024 Apr 9.
Treatment options for COVID-19 remain limited. Here, we report the optimization of an siRNA targeting the highly conserved leader region of SARS-CoV-2. The siRNA was rendered nuclease resistant by the introduction of modified nucleotides without loss of activity. Importantly, the siRNA also retained its inhibitory activity against the emerged omicron sublineage variant BA.2, which occurred after the siRNA was designed and is resistant to other antiviral agents such as antibodies. In addition, we show that a second highly active siRNA designed against the viral 5'-UTR can be applied as a rescue molecule, to minimize the spread of escape mutations. We therefore consider our siRNA-based molecules to be promising broadly active candidates for the treatment of current and future SARS-CoV-2 variants.
针对 COVID-19 的治疗选择仍然有限。在这里，我们报告了一种针对 SARS-CoV-2 高度保守的前导区的 siRNA 的优化。通过引入修饰核苷酸而不丧失活性，使 siRNA 具有抗核酸酶的能力。重要的是，该 siRNA 对出现的 omicron 亚谱系变异体 BA.2 也保持了抑制活性，BA.2 是在设计 siRNA 之后出现的，并且对其他抗病毒药物如抗体具有耐药性。此外，我们还表明，针对病毒 5'-UTR 设计的第二种高活性 siRNA 可用作挽救分子，以最大程度地减少逃逸突变的传播。因此，我们认为我们的基于 siRNA 的分子是治疗当前和未来 SARS-CoV-2 变体的有前途的广谱候选药物。
